Human Molecular Genetics Advance Access originally published online on May 5, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 13 1361-1371
DOI: 10.1093/hmg/ddh152
Human Molecular Genetics, Vol. 13, No. 13 © Oxford University Press 2004; all rights reserved
Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin
1Inserm U574 and 2Department of Genetics, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France and 3CNRS UPR 1929, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005 Paris, France
Received March 10, 2004; Accepted April 26, 2004
Cystinosis is an inherited disorder characterized by defective lysosomal efflux of cystine. Three clinical forms (infantile, juvenile and ocular cystinosis) have been described according to the age of onset and severity of the symptoms. The causative gene, CTNS, encodes a seven transmembrane domain protein, cystinosin, which we recently identified as a H+-driven cystine transporter using an in vitro transport assay. In this study, we explored the relationship between transport activity and intracellular localization of cystinosin mutants and their associated clinical phenotype. Thirty-one pathogenic mutations (24 missense mutations, seven in-frame deletions or insertions) were analysed. Most of the mutations did not alter the lysosomal localization of cystinosin, although three partially mislocalized the protein independently of its C-terminal sorting motif, thus confirming the presence of an additional sorting mechanism. Sixteen of 19 mutations associated with infantile cystinosis abolished transport, whereas three of five mutations associated with juvenile or ocular forms strongly reduced transport, in agreement with the milder clinical phenotype. Five atypical, unclassified or misclassified mutations could be clarified using the transport data and additional genetic information. Overall, our data demonstrate that, excluding premature termination of cystinosin, impaired transport is the most frequent cause of pathogenicity, with infantile cystinosis generally resulting from a total loss of activity. Thus the transport assay could be used as a prognostic tool when novel mutations are identified.
* To whom correspondence should be addressed at: Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, 1919 Route de Mende, 34293 Montpellier, France. Tel: +33 467613674; Fax: +33 467040231; Email: kalatzis{at}igm.cnrs-mop.fr
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